The independent role of vascular endothelium in the regulation of vascular tone was firstly stated in Furchgott and Zawadzki article published in Nature, 1980 . The authors revealed the ability of independent muscular tone changes in the isolated artery in response to acetylcholine, without participation of central (neuro-humoral) mechanisms.
Further studies confirm that endothelium is not a passive barrier between the blood and the tissues, but an active structure. Its dysfunction is inherent in the pathogenesis of almost any cardiovascular disorders, including atherosclerosis, hypertension, coronary heart disease (CHD), chronic heart failure (CHF). Moreover, it participates in the inflammatory reactions, autoimmune processes, diabetes, thromboses, sepsis, malignant growth etc. [1].
Normally, endothelial reaction consists in the increased production of substances that lead to the relaxation of smooth muscles of the vascular wall, primarily of nitric oxide (NO) and its derivatives (endothelial relaxation factors), together with prostacyclin and endothelium-dependent hyperpolarization factor. It should be noted that NO effects are not limited by local dilation, but include anti-proliferative effect on the vascular smooth muscles. Moreover, NO exerts several important systemic effects within the vascular lumen, including those protecting the vascular walls and preventing clots formation: blockade of platelet aggregation, of low-density lipoprotein (LDL) oxidation, of adhesion molecules expression, of monocytes and platelets adhesion to the vascular wall, of endothelin production. In certain cases, endothelium becomes a cause of vascular constriction, both due to reduced NO production and to the increased synthesis of vasoconstrictors (endothelial constriction factors): over-oxydized anions, vasoconstrictor prostenoids like thromboxane A2, and endothelin-1 (ET-1). Prolonged exposure to various damaging factors (hypoxia, intoxication, inflammation, haemodynamic overload) results in the gradual depletion and inversion of compensatory dilatation ability of endothelium, and predomination of vasoconstriction and endothelial proliferation in response to the usual stimuli. Chronic excessive activation of renin-angiotensin-aldosterone system (RAAS) is a most important factor of endothelial dysfunction. [1]
Nitric oxide molecule (NO) is a principal vasodilating agent. Normally, low levels of NO are continuously released from the endothelium and supports the dilatation of the vessels. Search of efficacious methods of correction of impaired endothelial functions in CHD patients is one of the important goals of modern cardiology. In this context, both experimental and practical medicine express interest to the studies of a physiological phenomenon named “preconditioning”. Preconditioning as a result of short episodes of ischemia-reperfusion leads to improved tissue resistance to ischemia. Various methods of preconditioning are available. Clinically, pharmacological preconditioning is preferable due to technological simplicity and absence of potential ischaemic danger for affected tissues. Among pharmacological substances, Nicorandil is one of the most promising humoral agents that take part in the implementation of preconditioning phenomenon. Nicorandil possesses favourable properties, such as the absence of adverse effects. Moreover, it is one of nitric oxide donators [2].
Staroseltseva O. A. et al. demonstrated significant endothelial and cardiac protection due to ischaemic preconditioning in the model of L-NAME-induced NO deficiency. This protection manifested in the reduction of endothelial dysfunction ratio (EDR) to 2.5±0.3 AU, prevention of NO level depression (4.8±0.29 mcmol/L) and of CRP increase (0.74±0.05 mg/dL), prevention of excessive adrenergic reactivity, and in the increase of cardiac contractility up to 87.1±6.4% during resistance testing; Nicorandil (4 mg/kg) preconditioning resulted in significant endothelial and cardiac protection in the model of L-NAME-induced NO deficiency, which resulted in EDR reduction to 1.76±0.18 AU, complete prevention of NO level reduction (6.2±0.25 mcmol/L) and of CRP increase (0.6±0.1 mg/dL), prevention of excessive adrenergic reactivity and increased myocardium contractility up to 77.2±8.3% during resistance testing. Pathomorphological studies revealed decreased occurrence of membranous glomerulopathy, cardiac myocyte hypertrophy and necrosis of cardiomyocytes, destructive changes of vascular endothelium and hypertrophy of vascular walls in the kidneys and in the myocardium. Glibenclamide (4 mg/kg) provided blockade of ATP-dependent potassium channels and neutralized protective effects of distant ischaemic preconditioning on the endothelium and on the heart, as well as of helium (inert gas) preconditioning, of pharmacological preconditioning with the use of Nicorandil in the model of L-NAME-induced NO deficiency. This resulted in EDR increase up to the values close to those in L-NAME group, in NO decrease and in the increase of C-reactive protein in any groups [2].
NO-synthase blockade due to 7-day-long administration of L-NAME is known to induce arterial hypertension (mean systolic blood pressure 191.3±7.1, mean diastolic BP 146.0±4.2 mm Hg) and 5-fold increase of endothelial dysfunction ratio. The effect of concomitant use of NO donator, L-arginine, and arginase inhibitors L-norvaline and nor-NONA, leading to the neutralization L-NAME-induced endothelial dysfunction, was demonstrated and resulted in EDR and blood pressure reduction. The most efficacious combination included L-arginine 70 mg/kg and L-norvaline 10 mg/kg in the longed-acting form with 12-hour release period.
One of the main physiological mechanisms of smooth muscle relaxation consists in the increase of cGMP (cyclic nucleotide) level. At present, NO-cGMP-dependent pathway of vascular relaxation is well studied. This pathway is mediated by the activation of soluble guanylate cyclase (sGC). Here, the drugs are used that are able to produce NO. This leads to rapid increase of cGMP level in the vascular smooth muscles for a short time. However, repeated NO-donator use leads to desensitization of NO-cGMP-dependent pathway and to the tolerance that results in their inefficacy in cases of long-term administration. Therefore, the search of mechanisms and drugs capable to activate sGC for a long time is one of the promising concepts in the physiology and pharmacology of cardiovascular system. In 1966, the hypotensive effect of oxatriazole derivatives in anaesthetized dogs was revealed. The mechanism of hypotensive effect of oxatriazolium-5-olate was not investigated.
One of oxatriazolium-5-olate derivatives, 3-(3-[1,2,4]-triazolo)-oxatriazolium-5-olate (AS-6), provides prolonged hypotensive effect in conscious SHR and Wistar rats. In the present study, the level of activation of purified sGC obtained of the rabbit's lungs, was examined for the purpose of assessing the biochemical mechanism of AS-6 effects. In vitro, AS-6 (100 mcmol/L) activates sGC up to 30-fold compared to the basal activity. sGC activation increases following AS-6 level increase, therefore, this effect is dose-dependent. Moreover, AS-6 provides activation of cGMP synthesis in the aorta of Wistar rats up to 13-fold level compared to baseline. Thus, AS-6 stimulated cGMP synthesis induced both by purified sGC and sGC in the aortic tissue. sGC activation is dose-dependent [3].
Recently, a significant importance is attributed to endothelial dysfunction as a possible cause of erectile dysfunction [4, 5]. This phenomenon leads to the loss of regulatory properties of endothelium, primarily of the ability to change the smooth muscle tone at the boundary of endothelium due to the local decrease of NO production. The key role of increased NO discharge in the start, development, and maintenance of erection is well established [6].
Moreover, the pharmaceutical agents used for improving sexual potency, are known [7].
However, such pharmaceutical agents cannot be used solely for the treatment of sexual disorders, and are applied for prophylactic purposes.
A pharmaceutical agent that improves sexual potency is available [8].
This pharmaceutical agent is rather used as required, and its administration is not for treatment purposes.
The closest analogue represents a pharmaceutical agent used to treat the sexual disorders [9].
However, this agent does not provide effective local NO production and any hypotensive effect, therefore, cannot be effective in the treatment of sexual disorders.